Genetic Test Scores Predicting Intelligence Are Not the New Eugenics
A thinking person.
"A world where people are slotted according to their inborn ability – well, that is Gattaca. That is eugenics."
This was the assessment of Dr. Catherine Bliss, a sociologist who wrote a new book on social science genetics, when asked by MIT Technology Review about polygenic scores that can predict a person's intelligence or performance in school. Like a credit score, a polygenic score is statistical tool that combines a lot of information about a person's genome into a single number. Fears about using polygenic scores for genetic discrimination are understandable, given this country's ugly history of using the science of heredity to justify atrocities like forcible sterilization. But polygenic scores are not the new eugenics. And, rushing to discuss polygenic scores in dystopian terms only contributes to widespread public misunderstanding about genetics.
Can we start genotyping toddlers to identify the budding geniuses among them? The short answer is no.
Let's begin with some background on how polygenic scores are developed. In a genome wide-association study, researchers conduct millions of statistical tests to identify small differences in people's DNA sequence that are correlated with differences in a target outcome (beyond what can attributed to chance or ancestry differences). Successful studies of this sort require enormous sample sizes, but companies like 23andMe are now contributing genetic data from their consumers to research studies, and national biorepositories like U.K. Biobank have put genetic information from hundreds of thousands of people online. When applied to studying blood lipids or myopia, this kind of study strikes people as a straightforward and uncontroversial scientific tool. But it can also be conducted for cognitive and behavioral outcomes, like how many years of school a person has completed. When researchers have finished a genome-wide association study, they are left with a dataset with millions of rows (one for each genetic variant analyzed) and one column with the correlations between each variant and the outcome being studied.
The trick to polygenic scoring is to use these results and apply them to people who weren't participants in the original study. Measure the genes of a new person, weight each one of her millions of genetic variants by its correlation with educational attainment from a genome-wide association study, and then simply add everything up into a single number. Voila! -- you've created a polygenic score for educational attainment. On its face, the idea of "scoring" a person's genotype does immediately suggest Gattaca-type applications. Can we now start screening embryos for their "inborn ability," as Bliss called it? Can we start genotyping toddlers to identify the budding geniuses among them?
The short answer is no. Here are four reasons why dystopian projections about polygenic scores are out of touch with the current science:
The phrase "DNA tests for IQ" makes for an attention-grabbing headline, but it's scientifically meaningless.
First, a polygenic score currently predicts the life outcomes of an individual child with a great deal of uncertainty. The amount of uncertainty around polygenic predictions will decrease in the future, as genetic discovery samples get bigger and genetic studies include more of the variation in the genome, including rare variants that are particular to a few families. But for now, knowing a child's polygenic score predicts his ultimate educational attainment about as well as knowing his family's income, and slightly worse than knowing how far his mother went in school. These pieces of information are also readily available about children before they are born, but no one is writing breathless think-pieces about the dystopian outcomes that will result from knowing whether a pregnant woman graduated from college.
Second, using polygenic scoring for embryo selection requires parents to create embryos using reproductive technology, rather than conceiving them by having sex. The prediction that many women will endure medically-unnecessary IVF, in order to select the embryo with the highest polygenic score, glosses over the invasiveness, indignity, pain, and heartbreak that these hormonal and surgical procedures can entail.
Third, and counterintuitively, a polygenic score might be using DNA to measure aspects of the child's environment. Remember, a child inherits her DNA from her parents, who typically also shape the environment she grows up in. And, children's environments respond to their unique personalities and temperaments. One Icelandic study found that parents' polygenic scores predicted their children's educational attainment, even if the score was constructed using only the half of the parental genome that the child didn't inherit. For example, imagine mom has genetic variant X that makes her more likely to smoke during her pregnancy. Prenatal exposure to nicotine, in turn, affects the child's neurodevelopment, leading to behavior problems in school. The school responds to his behavioral problems with suspension, causing him to miss out on instructional content. A genome-wide association study will collapse this long and winding causal path into a simple correlation -- "genetic variant X is correlated with academic achievement." But, a child's polygenic score, which includes variant X, will partly reflect his likelihood of being exposed to adverse prenatal and school environments.
Finally, the phrase "DNA tests for IQ" makes for an attention-grabbing headline, but it's scientifically meaningless. As I've written previously, it makes sense to talk about a bacterial test for strep throat, because strep throat is a medical condition defined as having streptococcal bacteria growing in the back of your throat. If your strep test is positive, you have strep throat, no matter how serious your symptoms are. But a polygenic score is not a test "for" IQ, because intelligence is not defined at the level of someone's DNA. It doesn't matter how high your polygenic score is, if you can't reason abstractly or learn from experience. Equating your intelligence, a cognitive capacity that is tested behaviorally, with your polygenic score, a number that is a weighted sum of genetic variants discovered to be statistically associated with educational attainment in a hypothesis-free data mining exercise, is misleading about what intelligence is and is not.
The task for many scientists like me, who are interested in understanding why some children do better in school than other children, is to disentangle correlations from causation.
So, if we're not going to build a Gattaca-style genetic hierarchy, what are polygenic scores good for? They are not useless. In fact, they give scientists a valuable new tool for studying how to improve children's lives. The task for many scientists like me, who are interested in understanding why some children do better in school than other children, is to disentangle correlations from causation. The best way to do that is to run an experiment where children are randomized to environments, but often a true experiment is unethical or impractical. You can't randomize children to be born to a teenage mother or to go to school with inexperienced teachers. By statistically controlling for some of the relevant genetic differences between people using a polygenic score, scientists are better able to identify potential environmental causes of differences in children's life outcomes. As we have seen with other methods from genetics, like twin studies, understanding genes illuminates the environment.
Research that examines genetics in relation to social inequality, such as differences in higher education outcomes, will obviously remind people of the horrors of the eugenics movement. Wariness regarding how genetic science will be applied is certainly warranted. But, polygenic scores are not pure measures of "inborn ability," and genome-wide association studies of human intelligence and educational attainment are not inevitably ushering in a new eugenics age.
Gene Transfer Leads to Longer Life and Healthspan
In August, a study provided the first proof-of-principle that genetic material transferred from one species to another can increase both longevity and healthspan in the recipient animal.
The naked mole rat won’t win any beauty contests, but it could possibly win in the talent category. Its superpower: fighting the aging process to live several times longer than other animals its size, in a state of youthful vigor.
It’s believed that naked mole rats experience all the normal processes of wear and tear over their lifespan, but that they’re exceptionally good at repairing the damage from oxygen free radicals and the DNA errors that accumulate over time. Even though they possess genes that make them vulnerable to cancer, they rarely develop the disease, or any other age-related disease, for that matter. Naked mole rats are known to live for over 40 years without any signs of aging, whereas mice live on average about two years and are highly prone to cancer.
Now, these remarkable animals may be able to share their superpower with other species. In August, a study provided what may be the first proof-of-principle that genetic material transferred from one species can increase both longevity and healthspan in a recipient animal.
There are several theories to explain the naked mole rat’s longevity, but the one explored in the study, published in Nature, is based on the abundance of large-molecule high-molecular mass hyaluronic acid (HMM-HA).
A small molecule version of hyaluronic acid is commonly added to skin moisturizers and cosmetics that are marketed as ways to keep skin youthful, but this version, just applied to the skin, won’t have a dramatic anti-aging effect. The naked mole rat has an abundance of the much-larger molecule, HMM-HA, in the chemical-rich solution between cells throughout its body. But does the HMM-HA actually govern the extraordinary longevity and healthspan of the naked mole rat?
To answer this question, Dr. Vera Gorbunova, a professor of biology and oncology at the University of Rochester, and her team created a mouse model containing the naked mole rat gene hyaluronic acid synthase 2, or nmrHas2. It turned out that the mice receiving this gene during their early developmental stage also expressed HMM-HA.
The researchers found that the effects of the HMM-HA molecule in the mice were marked and diverse, exceeding the expectations of the study’s co-authors. High-molecular mass hyaluronic acid was more abundant in kidneys, muscles and other organs of the Has2 mice compared to control mice.
In addition, the altered mice had a much lower incidence of cancer. Seventy percent of the control mice eventually developed cancer, compared to only 57 percent of the altered mice, even after several techniques were used to induce the disease. The biggest difference occurred in the oldest mice, where the cancer incidence for the Has2 mice and the controls was 47 percent and 83 percent, respectively.
With regard to longevity, Has2 males increased their lifespan by more than 16 percent and the females added 9 percent. “Somehow the effect is much more pronounced in male mice, and we don’t have a perfect answer as to why,” says Dr. Gorbunova. Another improvement was in the healthspan of the altered mice: the number of years they spent in a state of relative youth. There’s a frailty index for mice, which includes body weight, mobility, grip strength, vision and hearing, in addition to overall conditions such as the health of the coat and body temperature. The Has2 mice scored lower in frailty than the controls by all measures. They also performed better in tests of locomotion and coordination, and in bone density.
Gorbunova’s results show that a gene artificially transferred from one species can have a beneficial effect on another species for longevity, something that had never been demonstrated before. This finding is “quite spectacular,” said Steven Austad, a biologist at the University of Alabama at Birmingham, who was not involved in the study.
Just as in lifespan, the effects in various organs and systems varied between the sexes, a common occurrence in longevity research, according to Austad, who authored the book Methuselah’s Zoo and specializes in the biological differences between species. “We have ten drugs that we can give to mice to make them live longer,” he says, “and all of them work better in one sex than in the other.” This suggests that more attention needs to be paid to the different effects of anti-aging strategies between the sexes, as well as gender differences in healthspan.
According to the study authors, the HMM-HA molecule delivered these benefits by reducing inflammation and senescence (cell dysfunction and death). The molecule also caused a variety of other benefits, including an upregulation of genes involved in the function of mitochondria, the powerhouses of the cells. These mechanisms are implicated in the aging process, and in human disease. In humans, virtually all noncommunicable diseases entail an acceleration of the aging process.
So, would the gene that creates HMM-HA have similar benefits for longevity in humans? “We think about these questions a lot,” Gorbunova says. “It’s been done by injections in certain patients, but it has a local effect in the treatment of organs affected by disease,” which could offer some benefits, she added.
“Mice are very short-lived and cancer-prone, and the effects are small,” says Steven Austad, a biologist at the University of Alabama at Birmingham. “But they did live longer and stay healthy longer, which is remarkable.”
As for a gene therapy to introduce the nmrHas2 gene into humans to obtain a global result, she’s skeptical because of the complexity involved. Gorbunova notes that there are potential dangers in introducing an animal gene into humans, such as immune responses or allergic reactions.
Austad is equally cautious about a gene therapy. “What this study says is that you can take something a species does well and transfer at least some of that into a new species. It opens up the way, but you may need to transfer six or eight or ten genes into a human” to get the large effect desired. Humans are much more complex and contain many more genes than mice, and all systems in a biological organism are intricately connected. One naked mole rat gene may not make a big difference when it interacts with human genes, metabolism and physiology.
Still, Austad thinks the possibilities are tantalizing. “Mice are very short-lived and cancer-prone, and the effects are small,” he says. “But they did live longer and stay healthy longer, which is remarkable.”
As for further research, says Austad, “The first place to look is the skin” to see if the nmrHas2 gene and the HMM-HA it produces can reduce the chance of cancer. Austad added that it would be straightforward to use the gene to try to prevent cancer in skin cells in a dish to see if it prevents cancer. It would not be hard to do. “We don’t know of any downsides to hyaluronic acid in skin, because it’s already used in skin products, and you could look at this fairly quickly.”
“Aging mechanisms evolved over a long time,” says Gorbunova, “so in aging there are multiple mechanisms working together that affect each other.” All of these processes could play a part and almost certainly differ from one species to the next.
“HMM-HA molecules are large, but we’re now looking for a small-molecule drug that would slow it’s breakdown,” she says. “And we’re looking for inhibitors, now being tested in mice, that would hinder the breakdown of hyaluronic acid.” Gorbunova has found a natural, plant-based product that acts as an inhibitor and could potentially be taken as a supplement. Ultimately, though, she thinks that drug development will be the safest and most effective approach to delivering HMM-HA for anti-aging.
A new study provides key insights in what causes Alzheimer's: a breakdown in the brain’s system for clearing waste.
In recent years, researchers of Alzheimer’s have made progress in figuring out the complex factors that lead to the disease. Yet, the root cause, or causes, of Alzheimer’s are still pretty much a mystery.
In fact, many people get Alzheimer’s even though they lack the gene variant we know can play a role in the disease. This is a critical knowledge gap for research to address because the vast majority of Alzheimer’s patients don’t have this variant.
A new study provides key insights into what’s causing the disease. The research, published in Nature Communications, points to a breakdown over time in the brain’s system for clearing waste, an issue that seems to happen in some people as they get older.
Michael Glickman, a biologist at Technion – Israel Institute of Technology, helped lead this research. I asked him to tell me about his approach to studying how this breakdown occurs in the brain, and how he tested a treatment that has potential to fix the problem at its earliest stages.
Dr. Michael Glickman is internationally renowned for his research on the ubiquitin-proteasome system (UPS), the brain's system for clearing the waste that is involved in diseases such as Huntington's, Alzheimer's, and Parkinson's. He is the head of the Lab for Protein Characterization in the Faculty of Biology at the Technion – Israel Institute of Technology. In the lab, Michael and his team focus on protein recycling and the ubiquitin-proteasome system, which protects against serious diseases like Alzheimer’s, Parkinson’s, cystic fibrosis, and diabetes. After earning his PhD at the University of California at Berkeley in 1994, Michael joined the Technion as a Senior Lecturer in 1998 and has served as a full professor since 2009.
Dr. Michael Glickman